In the course of investigating biotransformation of Alzheimer's amyloid (-protein (A(), a hydrophobic protein, we have developed a micro-scale sample preparation procedure for analyzing soluble A( directly from biological fluid. In this micro-scale sample preparation, the immunoprecipitation technique was utilized to enhance the specificity and sensitivity for A( detection. This method was further developed for analyzing intracellular soluble and aggregate forms of A(s directly from cell lysates in the presence of detergents. Three type of detergents (nonionic, zwitterionic and anionic) were tested for the efficiency of solubilizing hydrophobic A(s and effect on mass spectrometric signal-to-noise ratio (S/N) of A( peaks. Our data showed that both Triton X-100 and CHAPS can efficiently lyse cells and solubilize A(s without harming the S/N of spectra. The nonionic detergent, N-octylglucoside (NOG), did not result useful spectra although NOG has been reported have no harmfu l effect on MALDI-MS assay for proteins. Our experimental results indicate that this micro-scale sample preparation method is a reliable method and should be a general and useful method for studying intracellular and hydrophobic proteins by MALDI-MS directly from complex biological preparations.